This invention is in the area of 2,5-disubstituted tetrahydrothiophenes, tetrahydrofurans, pyrrolidines and 1,3-disubstituted cyclopentanes. The compounds exhibit biological activity by inhibiting the enzyme 5-lipoxygenase.
Leukotrienes are potent local mediators, playing a major role in inflammatory and allergic responses, including arthritis, asthma, psoriasis, and thrombotic disease. Leukotrienes are straight chain eicosanoids produced by the oxidation of arachidonic acid by lipoxygenases. Arachidonic acid is oxidized by 5-lipoxygenase to the hydroperoxide 5-hydroperoxy-eicosatetraenoic acid (5-HPETE), that is converted to leukotriene A4, that in turn can be converted to leukotriene B4, C4, or D4. The slow-reacting substance of anaphylaxis is now known to be a mixture of leukotrienes C4, D4, and E4, all of which are potent bronchoconstrictors. There has been a research effort to develop specific receptor antagonists or inhibitors of leukotriene biosynthesis, to prevent or minimize pathogenic inflammatory responses mediated by these compounds.
European Patent Application Nos. 90117171.0 and 901170171.0 disclose indole, benzofuran, and benzothiophene lipoxygenase inhibiting compounds.
Recently, it was reported that the tetrahydrothiophene derivative of L-652,731, trans-2,5-bis-(3,4,5-trimethoxyphenyl)tetrahydrothiophene (L-653,150), is a potent PAF antagonist and a moderate inhibitor of 5-lipoxygenase. It has been disclosed that certain 2,5-diaryl tetrahydrothiophenes are PAF antagonists and leukotriene synthesis inhibitors. (Biftu, et al., Abstr. of 6th Int. Conf. on Prostaplandins and Related Compounds, Jun. 3-6, 1986, Florence, Italy; U.S. Pat. No. 4,757,084 to Biftu); WO 92/15294; WO 94/01430; WO 94/04537; and WO 94/06790.
WO 92/13848 discloses a class of racemic lipoxygenase inhibiting hydroxamic acid and N-hydroxyurea derivatives of the structure 
wherein R1 is hydrogen, alkyl, alkenyl, amino or substituted amino, R4 is hydrogen, a pharmaceutically acceptable cation, aroyl or alkoyl, A is alkylene or alkenylene, X is oxygen or sulfur, each Y is hydrogen, halo, cyano, alkyl, alkoxy, alkylthio, alkenyl, alkoxyalkyl, cycloalkyl, cycloalkyl, aryl, aryloxy, arylalkyl, arylalkenyl, arylalkoxy or substituted aryl, Z is oxygen or sulfur, m is 0 or 1, n is 1 to 5 and p is 2 to 6, inhibit the enzyme lipoxygenase.
Given the significant number of pathological immune and inflammatory responses that are mediated by 5-lipoxygenase, there remains a need to identify new compounds and compositions that inhibit this enzyme.
Therefore, it is an object of the present invention to provide compounds that reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals during an inflammatory or immune response.
It is another object of the present invention to provide pharmaceutical compositions for the treatment of pathological immune or inflammatory disorders mediated by 5-lipoxygenase.
It is another object of the present invention to provide a method for the treatment of pathological immune or inflammatory disorders mediated by products of 5-lipoxygenase.
Compounds of Formula I are provided 
wherein:
Ar is an aryl or heteroaryl group that is optionally substituted, preferably with halo (including but not limited to fluoro), lower alkoxy (including methoxy), lower aryloxy (including phenoxy), W, cyano, or R3;
m is 0 or 1;
n is 1-6;
W is independently xe2x80x94AN(OM)C(O)N(R3)R4, xe2x80x94N(OM)C(O)N(R3)R4, xe2x80x94AN(R3)C(O)N(OM)R4, xe2x80x94N(R3)C(O)N(OM)R4, xe2x80x94AN(OM)C(O)R4, xe2x80x94N(OM)C(O)R4xe2x80x94, AC(O)N(OM)R4, xe2x80x94C(O)N(OM)R4, or xe2x80x94C(O)NHA; A in lower alkyl, lower alkenyl, lower alkynyl, alkylaryl or arylalkyl groups, wherein one or more carbons optionally can be replaced by O, N, or S (with valence completed with hydrogen or oxygen as necessary), however, xe2x80x94Yxe2x80x94Axe2x80x94, xe2x80x94Axe2x80x94, or xe2x80x94AWxe2x80x94 should not include two adjacent heteroatoms (i.e. xe2x80x94Oxe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94Sxe2x80x94, xe2x80x94Oxe2x80x94Sxe2x80x94, etc.) (in one embodiment, lower alkyl is a branched alkyl group such as xe2x80x94(CH2)0C(alkyl)Hxe2x80x94, wherein n is 1-5, and specifically xe2x80x94(CH)2C(CH3)Hxe2x80x94, or lower alkynyl of the formula Cxe2x89xa1Cxe2x80x94CH(alkyl)-, including xe2x80x94Cxe2x89xa1Cxe2x80x94CH(CH3)xe2x80x94);
M is hydrogen, a pharmaceutically acceptable cation, or a metabolically cleavable leaving group;
X is O, S, S(O), S(O)2, NR3, or CHR5;
Y is O, S, S(O), S(O)2, NR3, or CHR5;
Z is O, SO S(O), S(O)2, NR3;
R1 and R2 are independently hydrogen, lower alkyl including methyl, cyclopropylmethyl, ethyl, isopropyl, butyl, pentyl hexyl, and C3-8 cycloalkyl, for example, cyclopentyl; halo lower alkyl, for example, trifluoromethyl; halo, for example fluoro; and xe2x80x94COOH;
R3 and R4 are independently hydrogen or alkyl, alkenyl, alkynyl, aryl, arylalkyl, alkylaryl, C1-6 alkoxy-C1-10 alkyl, C1-6 alkylthio-C1-10 alkyl, heteroaryl, or heteroarylalkyl-;
R5 is hydrogen, lower alkyl, lower alkenyl, lower alkynyl, arylalkyl, alkyaryl, xe2x80x94AN(OM)C(O)N(R3)R4, xe2x80x94AN(R3)C(O)N(OM)R4, xe2x80x94AN(OM)C(O)R4, xe2x80x94AC(O)N(OM)R4, xe2x80x94AS(O)xR3, xe2x80x94AS(O)aCH2C(O)R3, xe2x80x94AS(O)aCH2CR(OH)R4, or xe2x80x94AC(O)NHR3, wherein x is 0-2;
The Ar group, in one embodiment, is selected from the group consisting of phenyl, trimethoxyphenyl, dimethoxyphenyl, fluorophenyl (specifically 4-fluorophenyl), difluorophenyl, pyridyl, dimethoxypyridyl, quinolinyl, furyl, imidarolyl, and thienyl groups.
Nonlimiting examples of preferred compounds are: 
wherein R10 is halogen, xe2x80x94CN, hydrogen, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy, or lower aryloxy.
These compounds in general reduce the chemotaxis and respiratory burst leading to the formation of damaging oxygen radicals of polymorphonuclear leukocytes during an inflammatory or immune response. The compounds exhibit this biological activity by inhibiting the enzyme 5-lipoxygenase.
Another embodiment of the present invention is a pharmaceutical composition that includes an effective amount of a compound of Formula I or its pharmaceutically acceptable salt or derivative in combination with a pharmaceutically acceptable carrier for any of the disorders described herein.
A method to treat disorders mediated by 5-lipoxygenase is also disclosed, that includes administering an effective amount of one or more of the above-identified compounds or a pharmaceutically acceptable salt or derivative thereof, optionally in a pharmaceutically acceptable carrier.
It has been surprisingly determined that 5-lipoxygenase activity, oral availability, and stability in vivo (for example, glucuronidation rate) can vary significantly among the optical isomers of the disclosed compounds. Therefore, in one embodiment of the invention, the compound is administered in an enantiomerically enriched form, i.e., substantially in the form of one isomer.
Examples of immune, allergic and cardiovascular disorders include general inflammation, cardiovascular disorders including hypertension, skeletal-muscular disorders, osteoarthritis, gout, asthma, lung edema, adult respiratory distress syndrome, pain, aggregation of platelets, shock, rheumatoid arthritis, juvenile rheumatoid arthritis, psoriatic arthritis, psoriasis, autoimmune uveitis, allergic encephalomyelitis, systemic lupus erythematosis, acute necrotizing hemorrhagic encephalopathy, idiopathic thrombocytopenia, polychondritis, chronic active hepatitis, idiopathic sprue, Crohn""s disease, Graves ophthalmopathy, primary biliary cirrhosis, uveitis posterior, interstitial lung fibrosis; allergic asthma; and inappropriate allergic responses to environmental stimuli such as poison ivy, pollen, insect stings and certain foods, including atopic dermatitis and contact dermatitis.
The compounds disclosed herein can also be used as research tools to study biological pathways involving leukotrienes.
The following are nonlimiting examples of compounds that fall within Formula I. These examples are merely exemplary, and are not intended to limit the scope of the invention.
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-[4-Nxe2x80x2-methyl-Nxe2x80x2-hydroxyureidyl)butyl]tetrahydrofuran
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-[4-Nxe2x80x2-methyl-Nxe2x80x2-hydroxyureidyl)but-1-ynyl]tetrahydrofuran
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-methyl-Nxe2x80x2-hydroxyureidyl)butyl]tetrahydrofuran
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-methyl-Nxe2x80x2-hydroxyureidyl)but-1-ynyl]tetrahydrofuran
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-butyl-Nxe2x80x2-hydroxyureidyl)butyl]tetrahydrofuran
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-butyl-Nxe2x80x2-hydroxyureidyl)but-1-ynyl]tetrahydrofuran
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-[4-Nxe2x80x2methyl-N-hydroxyureidyl)butyl]tetrahydrofuran
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-[4-Nxe2x80x2-methyl-N-hydroxyureidyl)but-1-ynyl]tetrahydrofuran
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-methyl-N-hydroxyureidyl)butyl]tetrahydrofuran
trans-2-(4-flourophenoxymethyl)-5-[4-Nxe2x80x2-methyl-N-hydroxyureidyl)but-1-ynyl]tetrahydrofuran
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-butyl-N-hydroxyureidyl)butyl]tetrahydrofuran
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-butyl-N-hydroxyureidyl)but-1-ynyl]tetrahydrofuran
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-[4-Nxe2x80x2-methyl-Nxe2x80x2-hydroxyureidyl)butyl]tetrahydrothiophene
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-[4-Nxe2x80x2-methyl-Nxe2x80x2-hydroxyureidyl)but-1-ynyl]tetrahydrothiophene
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-methyl-Nxe2x80x2-hydroxyureidyl)butyl]tetrahydrothiophene
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-methyl-Nxe2x80x2-hydroxyureidyl)but-1-ynyl]tetrahydrothiophene
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-butyl-Nxe2x80x2-hydroxyureidyl)butyl]tetrahydrothiophene
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-butyl-Nxe2x80x2-hydroxyureidyl)but-1-ynyl]tetrahydrothiophene
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-[4-Nxe2x80x2-methyl-N-hydroxyureidyl)butyl]tetrahydrothiophene
trans-2-(3,4,5-trimethoxyphenoxymethyl)-5-[4-Nxe2x80x2-methyl-N-hydroxyureidyl)but-1-ynyl]tetrahydrothiophene
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-methyl-N-hydroxyureidyl)butyl]tetrahydrothiophene
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-methyl-N-hydroxyreidyl)but-1-ynyl]tetrahydrofuran
trans-2-(4-flourophenoxymethyl)-5-[4-Nxe2x80x2-hydroxyureidyl)butyl]tetrahydrothiophene
trans-2-(4-fluorophenoxymethyl)-5-[4-Nxe2x80x2-butyl-N-hydroxyureidyl)but-1-ynyl]tetrahydrothiophene
Further nonlimiting examples of other compounds that fall within Formula I are set forth below in Table 1.